Requirement for Abl Kinases in T Cell Receptor Signaling

Zipfel, Patricia A.; Zhang, Weiguo; Quiroz, Marisol; Pendergast, Ann Marie

doi:10.1016/j.cub.2004.07.021

Cited by 107 publications

(115 citation statements)

References 37 publications

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“…The CrkL protein has been observed with a total of 28 PTMs identified in MS experiments (see www.phosphosite.org), however only phosphorylated tyrosine 207 (pTyr207) has been validated (using a range of methods including western blot, site-directed mutatgenesis and flow cytometry 30,[49][50][51][52][53][54] ). Tyrosine 207 phosphorylation has been shown to be the principle phosphorylation event related to BCR-ABL activity 30 .…”

Section: Anticipated Resultsmentioning

confidence: 99%

Antibody-based detection of protein phosphorylation status to track the efficacy of novel therapies using nanogram protein quantities from stem cells and cell lines

et al. 2014

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This protocol describes a highly reproducible antibody-based method providing protein level and phosphorylation status information from nanogram quantities of protein cell lysate. Nanocapillary isoelectric focusing (cIEF) combines with UV activated linking chemistry to detect changes in phosphorylation status. We describe how to detect changes in response to tyrosine kinase inhibitors (TKIs) in the phosphorylation status of the adapter protein CrkL a major substrate of the oncogenic tyrosine kinase BCR/ABL in chronic myeloid leukaemia (CML), using highly enriched CML stem cells and mature cell populations in vitro. This protocol provides a 2.5pg/nL limit of protein detection (<0.2% of a stem cell sample containing <10 4 cells). Additional assays are described for pTyr207-CrkL and PTPRC/CD45, developed using this protocol and applied to CML patient samples. This method is high throughput and can act as a screen for in vitro cancer stem cell response to drugs and novel agents. SummaryThis protocol uses a highly sensitive and reproducible antibody-based capillary isoelectric focusing approach to establish protein phosphorylation status from nanogram quantities of protein cell lysate from cell line or primary stem cell material. Is-protocol-to

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Section: Anticipated Resultsmentioning

confidence: 99%

Antibody-based detection of protein phosphorylation status to track the efficacy of novel therapies using nanogram protein quantities from stem cells and cell lines

et al. 2014

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“…38 A recent study has described the requirement of ABL kinases in TCR signal transduction. 11 Imatinib, by inactivating c-ABL, led to decreased phosphorylation of ZAP70 and LAT. This resulted in reduced activation of transcription factors, causing a decreased T-cell expansion.…”

Section: Discussionmentioning

confidence: 99%

“…The involvement of ABL kinases in TCR signal transduction and T-cell viability is further confirmed by ABL-deficient mice, which show thymic and splenic atrophy and substantial T-and B-cell lymphopenia. 9,11 However, there are currently no indications that c-ABL may be regulated differently in naive and memory CTLs. In contrast, another study has reported that in memory CD8 ϩ T cells Lck expression is increased and associated with the CD8 coreceptor, whereas in naive CD8 ϩ T cells Lck is homogenously distributed in the cytoplasm and must first be recruited to the CD8 coreceptor upon TCR stimulation.…”

Section: Discussionmentioning

confidence: 99%

“…12 However, primary T cells lacking functional ABL TKs showed decreased IL-2 production and cell proliferation in response to TCR stimulation. 11 Comparably, it has been shown that ABL phosphorylates the BCR coreceptor CD19, suggesting a role for ABL in the regulation of B-cell proliferation. 13 Taken together, these experiments suggest that imatinib treatment in vivo may crucially influence antiviral CD8 ϩ T-and B-cell responses.…”

Section: Introductionmentioning

confidence: 99%

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Imatinib mesylate selectively impairs expansion of memory cytotoxic T cells without affecting the control of primary viral infections

Mumprecht

Matter

Pavelic

et al. 2006

Blood

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IntroductionImatinib mesylate (STI571, Glivec; Novartis Pharma AG, Basel, Switzerland) selectively inhibits the tyrosine kinases (TKs) ABL, BCR/ABL, ARG, PDGF-R ␣ and ␤, and c-KIT. Constitutive activation of these TKs has been documented in chronic myeloid leukemia (CML), Philadelphia chromosome-positive (Ph ϩ ) acute lymphocytic leukemia, myeloproliferative disorders due to chromosomal rearrangements in PDGF-R, and gastrointestinal stromal tumors with mutations in c-KIT. [1][2][3][4] In these diseases, blocking of TKs with imatinib is very efficient and substantially improves clinical outcome.Since TKs are involved in various intracellular signaling pathways, it is not surprising that imatinib treatment affects immune responses. Clinical observations have suggested that imatinib treatment correlates with a reversible dose-dependent lymphopenia and hypogammaglobulinemia. 5 Experimental in vitro studies have demonstrated that imatinib inhibited the development of human CD34 ϩ progenitor cell-derived dendritic cells (DCs). In addition, DCs exposed to imatinib were less potent in inducing cytotoxic T-cell (CTL) responses against tumor and recall antigens. 6 However, results of the effect of imatinib on DC maturation are controversial. Other experiments have suggested a normal maturation but reduced expansion of DCs in mice when stimulated with Flt3L. 7 Further, it has been shown that treating DCs in vitro with imatinib enhanced antigen-presenting cell function and overcame tumor-induced CD4 ϩ T-cell tolerance. 8 In addition, several in vitro studies using T cells isolated from human peripheral blood have demonstrated a dose-dependent reduction of T-cell proliferation in the presence of imatinib. 1,9,10 These results raise the possibility that imatinib could affect normal immune functions through TK inhibition. TKs play a prominent role in T-cell receptor (TCR) and B-cell receptor (BCR) signal transduction, and, thus, it is conceivable that imatinib may interfere with this process. TCR ligation triggers a signaling cascade that includes activation of the TKs Lck, ZAP70, and Ltk. A recent study has reported the requirement of c-ABL and ARG TKs for TCR-dependent transcriptional activation. 11 c-ABL is activated by Lck and then leads to the phosphorylation of ZAP70. It remains unclear whether c-ABL activates only ZAP70 or also activates other downstream proteins. 12 However, primary T cells lacking functional ABL TKs showed decreased IL-2 production and cell proliferation in response to TCR stimulation. 11 Comparably, it has been shown that ABL phosphorylates the BCR coreceptor CD19, suggesting a role for ABL in the regulation of B-cell proliferation. 13 Taken together, these experiments suggest that imatinib treatment in vivo may crucially influence antiviral CD8 ϩ T-and B-cell responses. However, physiologic consequences of imatinib treatment on protective immune response have not yet been demonstrated.Primary infection with lymphocytic choriomeningitis virus (LCMV), a noncytopathic RNA virus, is controlled almost ex...

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“…These agents cause growth arrest, apoptosis and decreased cell migration in EGFR-expressing basal keratinocytes through inhibition of the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)-Akt and Janus kinase (JAK)-STAT (signal transducer and activator of transcription) pathways 98 . Finally, imatinib has significant but pleiotropic effects on the immune system, including inhibition of T-cell proliferation and activation [99][100][101][102][103] , impaired monocyte 104 and natural killer cell 105 function, and increased antigen presentation by dendritic cells 106 . The target or targets underlying these effects are unclear, but may include ABL1/2 and/or the T-cell-receptor-associated tyrosine kinases ZAP70 and SYK.…”

Section: Box 2 | Non-cardiac Toxicity With Tyrosine-kinase-targeting mentioning

confidence: 99%

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

2007

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Requirement for Abl Kinases in T Cell Receptor Signaling

Abstract: We conclude that the Abl kinases have a role in the regulation of TCR-mediated signal transduction leading to IL-2 production and cell proliferation.

Cited by 107 publications

References 37 publications

Antibody-based detection of protein phosphorylation status to track the efficacy of novel therapies using nanogram protein quantities from stem cells and cell lines

Antibody-based detection of protein phosphorylation status to track the efficacy of novel therapies using nanogram protein quantities from stem cells and cell lines

Imatinib mesylate selectively impairs expansion of memory cytotoxic T cells without affecting the control of primary viral infections

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

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